Chaihu Longgu Muli Decoction for post-stroke insomnia: A protocol for systematic review and meta-analysis

Background: Poststroke insomnia (PSI) is a frequent complication of stroke usually as a comorbidity of poststroke depression and mainly occurs within the first 6 months after stroke.[1] Addressing PSI to improve stroke prognosis is of great value. Herbal medicine like Chaihu Longgu Muli Decoction (CLMD), which is commonly considered to be a good treatment for depression and epilepsy, has the therapeutic potential on PSI; however, insufficient systematic reviews were conducted to testify its efficacy. Therefore, the objective of this paper is to provide reliable evidence of the efficacy and safety of CLMD on PSI and a foundation for further investigation. Methods: The literature of clinical randomized controlled trials (RCTs) regarding CLMD for PSI published before June of 2021 will be retrieved in the databases, and 2 investigators will be asked to collect and crosscheck the data independently. For the including studies, the quality evaluation on methodology will be assessed in the light of the Cochrane Handbook for Systematic Review of Interventions V.5.1.0 as well as the quality of evidence will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation. Besides, the assessment of heterogeneity and reporting bias, the sensitivity analysis and the subgroup analysis will be conducted. Stata 15 will be applied to analyze the above data. Results: The review will conduct a high-quality synthesis on present evidence of CLMD for PSI. Conclusion: The conclusion of the study will indicate whether CLMD is effective and safe for PSI.


Description of the condition
Poststroke insomnia (PSI), known to be both a risk factor and complication of stroke, can negatively impact the prognosis and functional recovery after stroke. [2,3] According to the standard diagnostic criteria, insomnia is described as the difficulty in starting or maintaining sleep or early morning awakening which affects daytime functioning. Symptoms above should last over 3 months and at least 3 nights a week. [4] One meta-analysis indicated pooled prevalence of 38.2% with 40.70% of studies using nondiagnostic tools and 32.21% of which using diagnostic assessment tools. [5] Another reported that the incidence of PSI ranged from 25% to 82% which indicates the high variability of the prevalence of PSI. [6][7][8] For pharmacological therapy, Western medicine has few ideal therapeutic drugs. Benzodiazepines, antidepressants such as mianserin and hypnotics are not recommended, and though Zolpidem can relatively increase brain-derived neurotrophic factor secretion and protect the neurovascular unit in acute stroke, it is related to ischemic stroke risk. [9] On the contrary, there is much room for Traditional Chinese Medicine. The alternatives are in varied forms, such as acupuncture, massage, auricular acupoint, catgut embedment in acupoint, the music of 5 phases, Tai Chi, also the decoction including Si Ni San, Tianma Gouteng Yin, Da Ding Feng Zhu, Gui Pi Decoction, Chaihu Longgu Muli Decoction (CLMD), self-designed Ningxin Anshen Formula and so on. [10][11][12][13][14] Especially, Herbal medicine shows a significant efficacy in relieving insomnia. [15] Other treatments like cognitive-behavioral therapy, bright light therapy are also mentioned. [16,17] Recognized classification or clinical diagnostic criteria like DSM-IV/V, ICSD-2, ICD-10 are applied to assess symptoms of insomnia. Other instruments such as Pittsburgh Sleep Quality Index, Hamilton XH and YX contributed equally to this work.

This work is supported by Science and Technology Project of Jiangxi Provincial Health Commission (20197034). Medicine
Depression Scale, Epworth Sleepiness Scale or self-reported insomnia are also involved. [18] In addition, polysomnogram signals and the improved single-channel electroencephalogram signals are used to detect the sleep stages and sleep disorders, [19] and ISI-3 is also applicable as a brief screening tool for insomnia. [20]

Description of the intervention
According to the theory of Chinese Medicine, the possible mechanism of PSI can be interpreted as the disorderly qi flowing caused by the liver losing its dominant position of harmonizing qi. The constrained qi transforms into fire and disturb the spirit, which leads to sleep disorder. [12] CLMD, a classic prescription from "Treatise on Febrile Diseases," is conventionally applied in the situation of fullness in the chest, irritability with occasional attacks of palpitations, delirious speech and other symptoms belong to the property of fire. Nowadays its application has been widen to treat nervous system diseases including PSI by its weighing down and calming the floating spirit. Hence, this formula may be used in treating such biomedically-defined disorders as neurosis, schizophrenia, depression, hysteria, epilepsy, hypertension, hyperthyroidism, and postconcussion syndrome. [21][22][23] In terms of recent researches, despite a risk of bias from the studies included, CLMD showed great potential to be an alternative treatment for PSI compared with conventional medications. [24]

Possible mechanism of the intervention
According to "Huang Di Nei Jing," the basic pathogenesis of stroke is the imbalance of yin and yang, ying and wei, the rebellion and the offense of qi and blood, and the invasion of pathogenic factors on the brain. It can be described in detail that with a basic dysfunction of 5 internal organs, "phlegm, fire, stasis, qi, blood" pathological factors are generated. These pathological factors often associate with each other both and above so that the smooth flowing of qi and blood is blocked and the disharmony between yin and yang occurs. [25] It results in the failure of yang to enter yin and internal injury of fatigue by which insomnia is caused. As assistant ingredients, Longgu and Muli is aimed at sleep disorder and profuse dreaming directly. Their properties and actions of mineral substances make floating yang in spirit subdued. Longgu can suppress fright and calm the mind and Muli can calm the liver, enrich yin and extinguish wind so that ying and yang, ying and wei levels can be harmonized. Fuling acts on the hand shaoyin heart channel to nourish the heart and calm the mind. Dahuang disperses stomach heat to address restless sleep caused by stomach disharmony. And Guizhi is discovered to have positive effect on improving insomnia symptoms due to its chemical composition of Cinnamic aldehyde, cinnamic acid, 2-methoxycinnamic acid. Ginseng Saponins which is found the active ingredients of Renshen, can significantly improve SSR and autonomic nerve function in patients with insomnia. Together with Fuling, it can strengthen the Spleen qi and ensure that it is not further injured by the treatment. [23,26] In terms of the modern pharmacology, some researches proposed that the formative mechanism of CLMD is possibly associated with the process of neuronal regeneration and apoptosis, sympathetic hyperactivity and inflammatory reaction, so that regulates the neuroendocrine system centered on hypothalamus pituitary adrenal axis. [27] Another claims that CLMD takes effect by regulating patient neurotransmitter level such as improving serum 5-HT and DA. [28] In short, CLMD could take effect on the treatment for PSI both from the perspective of Chinese medicine and Western medicine.

The importance of this review
Preliminary data suggest a high frequency of PSI and their association with a less favorable stroke outcome, while treatment data are scarce. [29] Currently, there are insufficient systematic reviews of CLMD for PSI, 10 experimental researches in Chinese and 1 meta-analysis in English are found. Furthermore, the dispersed researches, unregistered indicators, lack of key regulatory elements are the potential defects. Therefore, there is a necessity to update and improve the systematic review and meta-analysis of CLMD of PSI to offer high-quality evidence-based evidence and obtain better guide clinical practice. This paper will be performed on the basis of the latest literature from 5 comprehensive databases, in the hope that provide reliable evidence of the efficacy and safety of CLMD on PSI.

Materials and methods
The study will keep to the guide from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and has been registered in PROSPERO (CRD42021252526). The protocol will be structured following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines.

Eligibility criteria 2.2.1. Study characteristics.
Except for those references with incomplete or wrong data, all randomized controlled trials (RCTs) will be included, irrespective of publication status. Only studies in Chinese or English will be included.

Object of study.
Taking the recognized classification or clinical diagnostic criteria for insomnia diagnosis, like DSM-IV/V, ICSD-2, ICD-10, and the patients involved suffered from PSI. No age, sex or territory limit. Patients with other diseases combined would also be excluded.

Intervention measure.
The patients in control group receive routine western medicines, while those in treatment group were treated with CLMD. The plus and minus of CLMD must conform to the principles of Monarch, minister, assistant and guide in Traditional Chinese Medicine prescription. The medicine could come in a number of different forms, such as bolus, powder, plaster, pellet, tablet, oral liquid and so on.

Outcome
The primary outcome will be measured by Pittsburgh Sleep Quality Index. The secondary outcomes will be measured by Epworth Sleepiness Scale, Stroke Specific Quality of Life Scale and the safety index.

Search strategy
The following electronic databases will be systematically searched up to June 2021: Cochrane Central Register of Controlled Trials, Embase, PubMed, Web of Science, the Chinese National Knowledge Infrastructure, the Chinese Biomedical Literature Database, the Chinese Scientific Journal Database and the Wanfang Database. The key words for literature searching are "Chaihu Longgu Muli Decoction" and "Post-stroke insomnia." The search strategy for PubMed is shown in Table 1.
We would also search additional data through other sources: Hand searching, Conference proceeding, International Clinical Trials Registry Platform and Chinese Clinical Trial Registry.

Study selection
To screen all the studies, we will use the EndNote X9 to remove the duplicates. The potentially relevant studies will be first screened by 2 investigators (ZZ and ZC) independently according to the titles and the abstracts above. And the studies will be excluded when the studies are not human studies, not clinical trials or not related to PSI. Then we will read the full articles and the studies assessed as eligible will be included. By reading full text, some studies will be excluded for the following reasons: Not RCTs, Incorrect intervention, Intervention included other medical therapies, RCTs but does not fit the inclusion criteria, No data for extraction. Detailed screening process is shown in Figure 1.

Data collection
Data collection will be completed and crosschecked independently by 2 investigators. The extracted data mainly contain basic information, characteristics of trial subjects, intervention measures, results of the studies. In case of divergence, the third reviewer (GC) should participate in the discussion and help to solve the problems. If the data about the outcomes are insufficient, corresponding author of the study will be contacted by e-mail or telephone. We will only analyze the available data if enough information cannot be acquired in this way. The Table 1 Search strategy for the PubMed database.

#1 Post-stroke insomnia
#2 Stroke #3 Insomnia OR wakefulness OR agrypnia #4 Chaihu longgu muli decoction OR Chaihu Longgu Muli Decoction OR chai hu longgu muli decoction OR Chaihu Longgu Muli Tang OR chaihu longgu muli tang (#1 OR (#2 AND #3)) AND #4 Figure 1. PRISMA flow chart of study selection process. PRISMA = preferred reporting items for systematic reviews and meta-analyses. Medicine potential impact of missing data will be considered on the results of meta-analysis.

Quality evaluation on methodology
The risk of bias of the involved studies will be evaluated independently by 2 verifiers (TC and YL) applying the assessment tool based on the standard in the Cochrane Handbook for Systematic Review of Interventions V.5.1.0 (updated March 2011). [30] In order to determine the level of risk, the following items would be considered: random sequence, blinding or not, allocation concealment, blinding of outcome assessment, selective reporting, complete or not, other bias. Across the 7 domains, there are 3 grades ("high," "low," or "unclear") to assess the risk of bias of the studies. If we could not judge the study with high or low risk bias because it makes no mention, we regard it unclear risk of bias.

Statistic analysis
The data would be analyzed by using the Stata 15. The enumeration data will be shown as RR and the measurement data will be shown as MD. All the effect sizes will be expressed as 95% confidence intervals.

Assessment of heterogeneity
Heterogeneity will be assessed by I 2 statistics and χ 2 statistics. For purpose of testing the degree of the aberrance among the studies, heterogeneity assessed by I 2 statistics will be used. More than 50% deems to be substantial heterogeneity. If the tests for heterogeneity have no significant meaning (I 2 ≤ 50%), the fixed effect model would be used for data analysis. Otherwise, we would pool and analyze data using a random-effects model.

Assessment of reporting bias
Funnel plots will be performed to evaluate reporting bias. We will use funnel plots to detect potential reporting bias. Begg and Egger test will be used to assess the symmetry of the funnel plot and detect publication bias.

Sensitivity analysis
We will carry out a sensitivity analysis to examine the dependability of the results and check whether there are any particular study leading to an obvious heterogeneity. If yes, we would read over the study and find the reason. If not, that means the results are reliable.

Subgroup analysis
Subgroup analyses will be performed according to the following items: course of the treatment, ages of the patients: children or adults, the original or relative prescription of CLMD.

Quality of evidence
The certainty of evidence will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation. The following factors will be taken into consideration: limitations in the design, inconsistencies, indirect evidence, hidden error and selective publication of positive results. Evidence quality will be judged as high, moderate, low or very low.

Ethics and dissemination
Our aim is that this systematic review could be published in a peer-reviewed journal. The results will provide evidence regarding the efficacy and safety of CLMD in treating PSI. Participants' privacy not being involved, this systematic review will not require informed consent form.

Patient and public involvement
No patients or public will be involved.

Discussion
Insomnia as a common complication after cerebral apoplexy, can easily lead to negative emotions such as anxiety and depression, which is not conducive to the recovery of neurological function, leading to increased mortality and disability rates, and seriously affecting the quality of life. At present, the pathogenesis of PSI has not been clarified, and western medicine treatment plays a general role on PSI, along with more adverse reactions. [31] Western medicine has entered a bottleneck stage. On the other hand, traditional Chinese medicine regards that PSI is mostly caused by emotions and internal injuries of the body, so as to relieve depression and relieve liver. CLMD from Treatise on Febrile Diseases, has the effect of relieving yang and heat, relieving shaoyang, as well as calming the mind and tranquilizing the mind. [28] Clinical studies have reported that CLMD is significant for PSI. This study will systematically review the efficacy and safety of CLMD in the treatment of PSI, providing a new idea for the clinical treatment of PSI.